Hematopoiesis under telomere attrition at the single-cell resolution

Natthakan Thongon, Feiyang Ma, Andrea Santoni, Matteo Marchesini, Elena Fiorini, Ashley Rose, Vera Adema, Irene Ganan-Gomez, Emma M. Groarke, Fernanda Gutierrez-Rodrigues, Shuaitong Chen, Pamela Lockyer, Sarah Schneider, Carlos Bueso-Ramos, Guillermo Montalban-Bravo, Caleb A. Class, Kelly A. Soltysiak, Matteo Pellegrini, Ergun Sahin, Alison A. Bertuch, Courtney D. DiNardo, Guillermo Garcia-Manero, Neal S. Young, Karen Dwyer and Simona Colla ()
Additional contact information
Natthakan Thongon: The University of Texas MD Anderson Cancer Center
Feiyang Ma: University of Michigan
Andrea Santoni: The University of Texas MD Anderson Cancer Center
Matteo Marchesini: The University of Texas MD Anderson Cancer Center
Elena Fiorini: The University of Texas MD Anderson Cancer Center
Ashley Rose: The University of Texas MD Anderson Cancer Center
Vera Adema: The University of Texas MD Anderson Cancer Center
Irene Ganan-Gomez: The University of Texas MD Anderson Cancer Center
Emma M. Groarke: National Institutes of Health
Fernanda Gutierrez-Rodrigues: National Institutes of Health
Shuaitong Chen: The University of Texas MD Anderson Cancer Center
Pamela Lockyer: The University of Texas MD Anderson Cancer Center
Sarah Schneider: The University of Texas MD Anderson Cancer Center
Carlos Bueso-Ramos: The University of Texas MD Cancer Center
Guillermo Montalban-Bravo: The University of Texas MD Anderson Cancer Center
Caleb A. Class: The University of Texas MD Anderson Cancer Center
Kelly A. Soltysiak: The University of Texas MD Anderson Cancer Center
Matteo Pellegrini: University of California
Ergun Sahin: Baylor College of Medicine
Alison A. Bertuch: Baylor College of Medicine
Courtney D. DiNardo: The University of Texas MD Anderson Cancer Center
Guillermo Garcia-Manero: The University of Texas MD Anderson Cancer Center
Neal S. Young: National Institutes of Health
Karen Dwyer: The University of Texas MD Anderson Cancer Center
Simona Colla: The University of Texas MD Anderson Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells’ self-renewal capabilities and eventually leads to their exhaustion. Mechanistically, we demonstrate that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes interferon signaling activation in telomere-dysfunctional hematopoietic stem cells and these cells’ skewed differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of hematopoietic stem cells by inducing apoptosis, autophagy, or senescence, and suggests that targeting IFI16 signaling axis might prevent hematopoietic stem cell functional decline in conditions affecting telomere maintenance.

Date: 2021
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-27206-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27206-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-27206-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().